The objective of the proposed research is to prepare synthetic analogs of polymyxin, and to determine their biological properties in order to develop structure-action and structure-toxicity relationships. The knowledge gained will be used in the development of clinically superior polymyxins for use in the treatment of systemic infections due to Pseudomonas aeruginosa and other gram-negative pathogens. The analogs to be synthesized will involve systematic variations in the number, strength, and distribution of basic groups and in the degree and distribution of lipophilic character in the polymyxin molecule. Synthesis of the analogs is being carried out by several routes, both in solution and on solid supports. The analogs will be tested for antibacterial activity in vitro against several pathogenic organisms, and in mice with systemic Pseudomonas aeruginosa infections. LD50 values will be measured in Swiss mice as an indication of the analogs' respiratory depressant potential. Nephrotoxicity will be assessed in Wistar rats by measuring increases in blood urea nitrogen or urinary protein.